WO2011112186A1 - Composés destinés au traitement de l'hépatite c - Google Patents

Composés destinés au traitement de l'hépatite c Download PDF

Info

Publication number
WO2011112186A1
WO2011112186A1 PCT/US2010/026786 US2010026786W WO2011112186A1 WO 2011112186 A1 WO2011112186 A1 WO 2011112186A1 US 2010026786 W US2010026786 W US 2010026786W WO 2011112186 A1 WO2011112186 A1 WO 2011112186A1
Authority
WO
WIPO (PCT)
Prior art keywords
solvent
mmol
fluorophenyl
gradient
pyridine
Prior art date
Application number
PCT/US2010/026786
Other languages
English (en)
Inventor
Richard Pracitto
John F. Kadow
John A. Bender
Brett R. Beno
Katharine Grant-Young
Ying Han
Piyasena Hewawasam
Andrew Nickel
Kyle E. Parcella
Kap-Sun Yeung
Louis S. Chupak
Original Assignee
Bristol-Myers Squibb Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to PCT/US2010/026786 priority Critical patent/WO2011112186A1/fr
Priority to JP2012557016A priority patent/JP5572725B2/ja
Priority to EP10708084.8A priority patent/EP2545050B1/fr
Priority to CN2010800667299A priority patent/CN102906089A/zh
Publication of WO2011112186A1 publication Critical patent/WO2011112186A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the disclosure generally relates to the novel compounds of formula I, II, III, rv, and V, including their salts, which have activity against hepatitis C virus (HCV) and are useful in treating those infected with HCV.
  • HCV hepatitis C virus
  • the disclosure also relates to compositions and methods of using these compounds.
  • Hepatitis C virus (HCV) is a major human pathogen, infecting an estimated
  • HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5 '-untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame.
  • the single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases.
  • ORF open reading frame
  • the first one is believed to be a metalloprotease and cleaves at the NS2-NS3 junction; the second one is a serine protease contained within the N-terminal region of NS3 (also referred to as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites.
  • the NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components.
  • NS5B (also referred to as HCV polymerase) is a RNA-dependent RNA polymerase that is involved in the replication of HCV.
  • the HCV NS5B protein is described in "Structural Analysis of the Hepatitis C Virus RNA Polymerase in Complex with Ribonucleotides
  • HCV-796 an HCV NS5B inhibitor
  • HCV-796 showed an ability to reduce HCV RNA levels in patients.
  • the viral RNA levels decreased transiently and then rebounded during dosing when treatment was with the compound as a single agent but levels dropped more robustly when combined with the standard of care which is a form of interferon and ribavirin.
  • the development of this compound was suspended due to hepatic toxicity observed during exteneded dosing of the combination regimens.
  • US patent 7,265, 152 and the corresponding PCT patent application WO2004/041201A2 describe compounds of the HCV-796 class.
  • the invention provides technical advantages, for example, the compounds are novel and are effective against hepatitis C. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.
  • One aspect of the invention is a compound of formula I, II, III, IV, or V
  • R 1 is halo, alkyl, cycloalkyl, alkoxy, oxazolidinonyl, dioxothiazinyl, R 5 R 6 N,
  • CONR 7 R 8 s piperidinonyl substituted with 1 substituent, pyrrolyl
  • phenyl is also substituted with 0-2 halo, alkyl, alkoxy, pyridinyl, phenyl or halophenyl substituents;
  • R 2 is hydrogen, halo, alkyl, cycloalkyl, alkoxy, or R ⁇ N;
  • R is cyano, alkoxycarbonyl, (cycloalkyl)oxycarbonyl, (alkylsulfonyl)aminocarbonyl, CONR n R 12 , (R 13 )(R 14 )NCONH, triazolyl, thiazolyl, or tetrazolyl;
  • R 4 is phenyl substituted with 0-2 halo
  • R 5 is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, benzyl, alkylcarbonyl, haloalkylcarbonyl, phenylcarbonyl, (alkoxyphenyl)carbonyl, alkylsulfonyl, phenylsulfonyl, (alkoxyphenyl)sulfonyl or (haloalkoxyphenyl)sulfonyl;
  • R 6 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; or R 5 and R 6 taken together with the nitrogen to which they are attached is oxazolidinonyl or dioxothiazinyl;
  • R 7 is hydrogen, alkyl, * ⁇ R 5 , 0 r * ⁇ Ar 1 ⁇
  • R 8 is hydrogen or alkyl
  • R 9 is hydrogen or alkyl
  • R 10 is hydrogen or alkyl
  • R 9 and R 10 taken together is ethylene, propylene, butylene, or pentylene
  • R 11 is hydrogen or alkyl
  • R 12 is hydrogen or alkyl; or R 1 1 and R 12 taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 1 is hydrogen or alkyl
  • R 14 is hydrogen or alkyl; or R 13 and R 14 taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 15 is alkyl or cycloalkyl
  • R 16 is hydrogen, halo, alkyl, or alkoxy
  • R 17 is hydrogen, halo, alkyl, or alkoxy
  • Ar 1 is isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, or phenyl, and is substituted with 0-1 halo, alkyl, or phenyl substituents; or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a compound of formula I, II, III, IV, or V where
  • R 1 is halo, alkoxy, oxazolidinonyl, dioxothiazinyl, R 5 R 6 N, or phenyl where said phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, and CONR 7 R 8 , and where said phenyl is substituted with 0-1 alkyl substituents;
  • R 2 is hydrogen, halo, alkoxy, or R ⁇ N;
  • R 3 is cyano, alkoxycarbonyl, (cycloalkyl)oxycarbonyl, (alkylsulfonyl)aminocarbonyl, CONR n R 12 , (R 13 )(R 14 )NCONH, triazolyl, thiazolyl, or tetrazolyl;
  • R 4 is phenyl substituted with 0-2 halo
  • R 5 is alkylsulfonyl
  • R 6 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl
  • R is hydrogen, alkyl, or * Ar ;
  • R 8 is hydrogen or alkyl;
  • R 9 is hydrogen or alkyl;
  • R 10 is hydrogen or alkyl; or R 9 and R 10 taken together is ethylene, propylene, butylene, or pentylene; R 11 is hydrogen or alkyl;
  • R is hydrogen or alkyl; R is hydrogen or alkyl;
  • R 14 is hydrogen or alkyl; or R 13 and R 14 taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • Ar 1 is phenyl or pyridinyl; or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a compound of formula I, II, III, IV, or V where
  • R 1 is alkoxy or phenyl where said phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, and CONR 7 R 8 , and where said phenyl is also substituted with 0-2 alkyl substituents;
  • R 2 is hydrogen, halo or R 5 ⁇ 6 ⁇ ;
  • R 3 is CONR 13 R 14 ;
  • R 4 is phenyl substituted with 0-2 halo
  • R 5 is alkylsulfonyl
  • R 6 is hydrogen or hydroxyalkyl
  • R 7 is hydrogen, alkyl, or "Ar 1 ⁇
  • R 8 is hydrogen
  • R 9 is alkyl
  • R 1U is alkyl; or R 9 and R 10 taken together is ethylene or propylene;
  • R is hydrogen or alkyl
  • R is hydrogen or alkyl
  • R is hydrogen or alkyl; or R 13 and R 14 taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 16 is hydrogen
  • R 17 is hydrogen
  • Ar 1 is pyridinyl or phenyl, and is substituted with 0-1 alkyl or phenyl substituents; or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a compound of formula I, II, III, IV, or V where R 1 is cycloalkyl, alkoxy, CONR 7 R 8 ? piperidinonyl substituted with 1
  • R 3 is CONR n R 12 ;
  • R 4 is phenyl substituted with 0-2 halo
  • R 5 is hydrogen, (cycloalkyl)alkyl, benzyl, haloalkylcarbonyl,
  • R 6 is hydrogen or hydroxyalkyl
  • R 7 is hydrogen, alkyl, ⁇
  • R 8 is hydrogen
  • R 9 is alkyl;
  • R 1U is alkyl; or
  • R 9 and R 10 taken together is ethylene or propylene;
  • R 11 is alkyl; R is hydrogen;
  • R 15 is alkyl or cycloalkyl
  • R 16 is hydrogen
  • R 17 is hydrogen
  • Ar 1 is isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, or phenyl, and is substituted with 0-1 alkyl or phenyl substituents; or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a compound of formula la, Ila, Ilia, IVa, or
  • R is halo, alkoxy, oxazolidinonyl, dioxothiazinyl, R ' 5 R 6 N, or phenyl where phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, and CONR 7 R 8 , and where phenyl is substituted with 0-1 alkyl substituent;
  • R 2 is hydrogen, halo, alkoxy, or R ⁇ 'TSi;
  • R 3 is cyano, alkoxycarbonyl, (cycloalkyl)oxycarbonyl, (alkylsulfonyl)aminocarbonyl, CONR n R 12 , (R 13 )(R 14 )NCONH, triazolyl, thiazolyl, or tetrazolyl;
  • R 4 is phenyl substituted with 0-2 halo;
  • R 5 is alkylsulfonyl
  • R 6 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl
  • R 7 is hydrogen, alkyl, or ⁇ hydrogen or alkyl
  • R 9 is hydrogen or alkyl
  • R is hydrogen or alkyl; or R 9 and R 10 taken together is ethylene, propylene, butylene, or pentylene; R 11 is hydrogen or alkyl;
  • R is hydrogen or alkyl; or R u and R 12 taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; and
  • R 13 is hydrogen or alkyl
  • R 14 is hydrogen or alkyl; or R 13 and R 14 taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; and
  • Ar 1 is phenyl or pyridinyl; or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a compound of formula la where R 1 R 17 are hydrogen.
  • Another aspect of the invention is a compound of formula Ila where R and 1 7 are hydrogen.
  • Another aspect of the invention is a compound of formula Ilia where R and R 17 are hydrogen.
  • Another aspect of the invention is a compound of formula IVa where R and 1 7 are hydrogen.
  • Another aspect of the invention is a compound of formula Va where R 16 and
  • R 1 is phenyl substituted with 1 CONR 7 R 8 substituent and 0-2 halo, alkyl, or alkoxy substituents
  • R 2 is hydrogen, halo, alkyl, or R 5
  • R R 3 is CONR n R 12 ;
  • R 4 is
  • R 5 is alkylsulfonyl
  • R 6 is alkyl
  • R 7 is * Al_
  • R 8 is hydrogen
  • R 9 is methyl
  • R 10 is methyl
  • R 9 and R 10 taken together is ethylene
  • R 11 is alkyl
  • R 12 is hydrogen or alkyl
  • R 16 is hydrogen
  • R 17 is hydrogen
  • Ar 1 is oxadiazolyl, pyridinyl, pyrimidinyl, or phenyl, and is substituted with 0-1 halo or alkyl substituents; or a pharmaceutically acceptable salt thereof.
  • R 1 is phenyl substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, carboxy, and CONR 7 R 8 , and where said phenyl is also substituted with 0-2 halo, alkyl, alkoxy, pyridinyl, phenyl or halophenyl substituents.
  • R 1 is phenyl substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, and CONR 7 R 8 , and where said phenyl is substituted with 0-1 halo, alkyl, or alkoxy substituents;
  • Another aspect of the invention is a compound of formula I, II, III, IV, or V where R 2 is R 5 ⁇ 6 ⁇ ;
  • Another aspect of the invention is a compound of formula I, II, III, IV, or V where R 3 is CONR n R 12 .
  • Another aspect of the invention is a compound of formula I, II, III, IV, or V where R 4 is phenyl or monofluorophenyl.
  • Another aspect of the invention is a compound of formula I, II, III, IV, or V where Ar 1 is phenyl.
  • any scope of any variable including R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , or Ar 1 can be used independently with the scope of any other instance of a variable.
  • Alkyl means a straight or branched alkyl group composed of 1 to 6 carbons.
  • Alkenyl means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond.
  • Cycloalkyl means a monocyclic ring system composed of 3 to 7 carbons.
  • Hydroalkyl means a monocyclic ring system composed of 3 to 7 carbons.
  • Hydroalkyl alkoxy
  • alkoxy alkoxy
  • alkoxy alkoxy
  • alkoxy straight and branched isomers composed of 1 to 6 carbon atoms for the alkyl moiety.
  • Haloalkyl and haloalkoxy include all halogenated isomers from monohalo substituted alkyl to perhalo substituted alkyl.
  • Aryl includes carbocyclic and heterocyclic aromatic substituents.
  • Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art.
  • a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.
  • Substituents which are illustrated by chemical drawing to bond at variable positions on a multiple ring system are intended to bond to the ring where they are drawn to append.
  • substituents R 1 and R 2 of formula IV are intended to bond to the benzene ring of formula IV and not to the thiophene ring.
  • Ethylene means ethanediyl or -CH 2 CH 2 -; propylene means propanediyl or -CH 2 CH 2 CH 2 -; butylene means butanediyl or -CH 2 CH 2 CH 2 CH 2 -; pentylene means pentanediyl or -CH2CH2CH2CH2CH2-.
  • the invention includes all pharmaceutically acceptable salt forms of the compounds.
  • Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, camsylate, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
  • Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
  • Some of the compounds of the invention possess asymmetric carbon atoms
  • the invention includes all stereoisomeric forms, including enantiomers and diastereomers as well as mixtures of stereoisomers such as racemates. Some stereoisomers can be made using methods known in the art. Stereoisomeric mixtures of the compounds and related intermediates can be separated into individual isomers according to methods commonly known in the art. The use of wedges or hashes in the depictions of molecular structures in the following schemes and tables is intended only to indicate relative stereochemistry, and should not be interpreted as implying absolute stereochemical assignments.
  • the invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.
  • the compounds may be made by methods known in the art including those described below and including variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials.
  • the variables (e.g. numbered "R" substituents) used to describe the synthesis of the compounds are intended only to illustrate how to make the compounds and are not to be confused with variables used in the claims or in other sections of the specification. The following methods are for illustrative purposes and are not intended to limit the scope of the invention.
  • some compounds of the invention may be prepared by coupling an aryl triflate or halide to a substituted phenyl boronic acid that in some examples contains a carboxylic acid or carboxylic acid ester.
  • Other coupling partner, techniques and conditions are known in the art as are other carbon-carbon bond forming reactions.
  • Acids and esters may be converted to amides by methods known in the art.
  • Bis-sulfonamides may be selectively hydrolyzed to a monosulfonamide.
  • the monosulfonamide may be alkylated again with either a simple or functionalized alkyl.
  • HCVNS5B RdRp cloning, expression, and purification The cDNA encoding the NS5B protein of HCV, genotype lb, was cloned into the pET2 la expression vector. The protein was expressed with an 18 amino acid C-terminal truncation to enhance the solubility.
  • the E. coli competent cell line BL21(DE3) was used for expression of the protein. Cultures were grown at 37 °C for ⁇ 4 hours until the cultures reached an optical density of 2.0 at 600 nm. The cultures were cooled to 20 °C and induced with 1 mM IPTG. Fresh ampicillin was added to a final
  • Cell pellets (3L) were lysed for purification to yield 15-24 mgs of purified NS5B.
  • the lysis buffer consisted of 20 mM Tris-HCl, pH 7.4, 500 mM NaCl, 0.5% triton X-100, 1 mM DTT, ImM EDTA, 20% glycerol, 0.5 mg/ml lysozyme, 10 mM MgC12, 15 ug/ml deoxyribonuclease I, and Complete TM protease inhibitor tablets (Roche). After addition of the lysis buffer, frozen cell pellets were resuspended using a tissue homogenizer.
  • aliquots of the lysate were sonicated on ice using a microtip attached to a Branson sonicator.
  • the sonicated lysate was centrifuged at 100,000 x g for lhr at 4 °C and filtered through a 0.2 ⁇ filter unit (Corning).
  • the protein was purified using three sequential chromatography steps:
  • the chromatography buffers were identical to the lysis buffer but contained no lysozyme, deoxyribonuclease I, MgC12 or protease inhibitor and the NaCl concentration of the buffer was adjusted according to the requirements for charging the protein onto the column.
  • Each column was eluted with a NaCl gradient which varied in length from 5-50 column volumes depending on the column type.
  • the resulting purity of the enzyme is >90% based on SDS-PAGE analysis.
  • the enzyme was aliquoted and stored at -80 °C.
  • HCV RdRp genotype lb assays were run in a final volume of 60 ⁇ in 96 well plates (Costar 3912).
  • the assay buffer is composed of 20 mM Hepes, pH 7.5, 2.5 mM KC1, 2.5 mM MgC12, 1 mM DTT, 1.6 U RNAse inhibitor (Promega N2515), 0.1 mg/ml BSA (Promega R3961), and 2 % glycerol. All compounds were serially diluted (3 -fold) in DMSO and diluted further in water such that the final concentration of DMSO in the assay was 2%.
  • HCV RdRp genotype lb enzyme was used at a final concentration of 28 nM.
  • a polyA template was used at 6 nM, and a biotinylated oligo-dT12 primer was used at 180 nM final concentration. Template was obtained commercially (Amersham 27- 41 10).
  • Biotinylated primer was prepared by Sigma Genosys. 3H-UTP was used at 0.6 ⁇ (0.29 ⁇ total UTP). Reactions were initiated by the addition of enzyme, incubated at 30 °C for 60 min, and stopped by adding 25 ⁇ of 50 mM EDTA containing SPA beads (4 ⁇ g/ ⁇ l, Amersham RPNQ 0007).
  • Modified HCVNS5B RdRp enzyme assay was performed essentially as described for the standard enzyme assay except for the following: The biotinylated oligo dT12 primer was precaptured on streptavidin- coated SPA beads by mixing primer and beads in assay buffer and incubating at room temperature for one hour. Unbound primer was removed after centrifugation. The primer-bound beads were resuspended in 20 mM Hepes buffer, pH 7.5 and used in the assay at final concentrations of 20 nM primer and 0.67 ⁇ g/ ⁇ l beads.
  • enzyme 14 nM was added to diluted compound followed by the addition of a mixture of template (0.2 nM) , 3H-UTP (0.6 ⁇ , 0.29 ⁇ ), and primer-bound beads, to initiate the reaction; concentrations given are final. Reactions were allowed to proceed for 4 hours at 30° C.
  • FRET Assay Preparation. To perform the HCV FRET screening assay, 96- well cell culture plates were used.
  • the FRET peptide (Anaspec, Inc.) (Taliani et al, Anal. Biochem. 1996, 240, 60-67) contains a fluorescence donor, EDANS, near one end of the peptide and an acceptor, DABCYL, near the other end.
  • the fluorescence of the peptide is quenched by intermolecular resonance energy transfer (RET) between the donor and the acceptor, but as the NS3 protease cleaves the peptide the products are released from RET quenching and the fluorescence of the donor becomes apparent.
  • RET intermolecular resonance energy transfer
  • the assay reagent was made as follows: 5X cell Luciferase cell culture lysis reagent from Promega (#E153A) diluted to IX with dH 2 0, NaCl added to 150 mM final, the FRET peptide diluted to 20 ⁇ final from a 2 mM stock.
  • HCV replicon cells with or without a Renilla luciferase reporter gene, were trypsinized and placed into each well of a 96-well plate with titrated test compounds added in columns 3 through 12; columns 1 and 2 contained a control compound (HCV protease inhibitor), and the bottom row contained cells without compound.
  • the plates were then placed in a CO 2 incubator at 37 °C. Assays. Subsequent to addition of the test compounds described above
  • FRET Assay Preparation at various times the plate was removed and Alamar blue solution (Trek Diagnostics, #00-100) was added per well as a measure of cellular toxicity. After reading in a Cytoflour 4000 instrument (PE Biosystems), plates were rinsed with PBS and then used for FRET assay by the addition of 30 ul of the FRET peptide assay reagent described above (FRET Assay Preparation) per well. The plate was then placed into the Cytoflour 4000 instrument which had been set to 340 excite/490 emission, automatic mode for 20 cycles and the plate read in a kinetic mode. Typically, the signal to noise using an endpoint analysis after the reads was at least three- fold.
  • Compound analysis was determined by quantification of the relative HCV replicon inhibition and the relative cytotoxicity values.
  • cytoxicity values the average Alamar Blue fluorescence signals from the control wells were set as 100% non-toxic. The individual signals in each of the compound test wells were then divided by the average control signal and multiplied by 100% to determine percent cytotoxicity.
  • HCV replicon inhibition values an average background value was obtained from the two wells containing the highest amount of HCV protease inhibitor at the end of the assay period. These numbers were similar to those obtained from naive Huh-7 cells.
  • the background numbers were then subtracted from the average signal obtained from the control wells and this number was used as 100% activity.
  • the individual signals in each of the compound test wells were then divided by the averaged control values after background subtraction and multiplied by 100% to determine percent activity.
  • EC5 0 values for a protease inhibitor titration were calculated as the concentration which caused a 50% reduction in FRET or luciferase activity.
  • the two numbers generated for the compound plate, percent cytoxicity and percent activity were used to determine compounds of interest for further analysis.
  • the HCV replicon luciferase assay was developed to monitor the inhibitory effects of compounds described in the disclosure on HCV viral replication.
  • HUH-7 cells constitutively expressing the HCV replicon, were grown in Dulbecco's Modified Eagle Media (DMEM) (Gibco-BRL) containing 10%> Fetal calf serum (FCS) (Sigma) and 1 mg/ml G418 (Gibco-BRL).
  • DMEM Dulbecco's Modified Eagle Media
  • FCS Fetal calf serum
  • CC50 values were generated by multiplexing the EnduRen-containing plates with Cell Titer-Blue (Promega, cat # G8082). 3 ⁇ of Cell-Titer Blue was added to each well and incubated for 8 hrs at 37°C. The fluorescence signal from each well was read, with an excitation wavelength at 525/10 nm and an emission wavelength of 598/10 nm, using the Viewlux Imager.
  • compositions and Methods of Treatment The compounds demonstrate activity against HCV NS5B and can be useful in treating HCV and HCV infection. Therefore, another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Another aspect of the invention is a composition further comprising a compound having anti-HCV activity.
  • compositions where the compound having anti-HCV activity is an interferon.
  • the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.
  • Another aspect of the invention is a composition where the compound having anti-HCV activity is a cyclosporin.
  • the cyclosporin is cyclosporin A.
  • compositions where the compound having anti-HCV activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'- monophospate dehydrogenase inhibitor, amantadine, and rimantadine.
  • Another aspect of the invention is a composition where the compound having anti-HCV activity is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.
  • a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.
  • compositions comprising a compound, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, an interferon and ribavirin.
  • Another aspect of the invention is a method of inhibiting the function of the HCV replicon comprising contacting the HCV replicon with a compound or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a method of inhibiting the function of the HCV NS5B protein comprising contacting the HCV NS5B protein with a compound or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof.
  • the compound is effective to inhibit the function of the HCV replicon.
  • the compound is effective to inhibit the function of the HCV NS5B protein.
  • Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, in conjunction with (prior to, after, or concurrently) another compound having anti-HCV activity.
  • Another aspect of the invention is the method where the other compound having anti-HCV activity is an interferon.
  • interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.
  • Another aspect of the invention is the method where the other compound having anti-HCV activity is a cyclosporin.
  • Another aspect of the invention is the method where the cyclosporin is cyclosporin A.
  • Another aspect of the invention is the method where the other compound having anti-HCV activity is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.
  • Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of a target selected from the group consisting of HCV metalloprotease, HCV serine protease, HCV
  • HCV helicase HCV NS4B protein
  • HCV entry HCV assembly
  • HCV egress HCV NS5A protein
  • IMPDH IMPDH
  • nucleoside analog for the treatment of an HCV infection.
  • Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of target in the HCV life cycle other than the HCV NS5B protein.
  • “Therapeutically effective” means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of hepatitis and HCV infection.
  • "Patient” means a person infected with the HCV virus and suitable for therapy as understood by practitioners in the field of hepatitis and HCV infection.
  • compositions comprised of a therapeutically effective amount of a compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients.
  • Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles.
  • Compositions encompass all common solid and liquid forms including for example capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. See, for example,
  • Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred.
  • dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg.
  • other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.
  • Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL.
  • Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.
  • agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL.
  • the invention encompasses all conventional modes of administration; oral and parenteral methods are preferred.
  • the dosing regimen will be similar to other agents used clinically. Typically, the daily dose will be 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, will be determined by a physician using sound medical judgement.
  • the invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in treating hepatitis and HCV infection.
  • the compound will generally be given in a daily dose of 1-100 mg kg body weight daily in conjunction with other agents.
  • the other agents generally will be given in the amounts used therapeutically.
  • the specific dosing regime will be determined by a physician using sound medical judgement.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 O / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 245 (MH + ).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, lOu, C18, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% methanol / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% methanol/ 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 362 (MH + ).
  • 3-(3-aminopyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide To a solution containing 3-(3-nitropyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide (2.0 g, 5.5 mmol) and methanol (18.5 mL) was added 10% Pd/C (1.6 g, 0.76 mmol, wet, 50% water) in one portion under a nitrogen atmosphere.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5u, CI 8, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 niM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 332 (MH + ).
  • LCMS retention time: 1.277 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5u, C18, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90%) CH 3 CN / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 410 (MH + ).
  • LCMS retention time: 2.403 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters- Sunfire, 5u, CI 8, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 645 (MH + ).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, lOu, C18, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% methanol / 90% ⁇ 2 0 / 10 mM TFA and solvent B was 10%) H 2 0 / 90%) methanol/ 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 631(MH + ).
  • Methyl 2-(4-fluorophenyl)-5-methoxypyrazolo[l,5-a]pyridine-3-carboxylate was prepared from 4-methoxypyridine (0.55 g, 3.1 mmol). 1H NMR (500 MHz,
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, lOu, CI 8, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% C3 ⁇ 4CN / 95% 3 ⁇ 40 / 10 mM ammonium acetate and solvent B was 5% H 2 0 / 95% CH 3 CN / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 301(MH + ).
  • 2-(4-fluorophenyl)-5-methoxy-N-methylpyrazolo[l,5-a]pyridine-3-carboxamide 2-(4-fluorophenyl)-5-methoxy-N-methylpyrazolo[l,5-a]pyridine-3-carboxamide was prepared from 2-(4-fluorophenyl)-5-methoxypyrazolo[l,5-a]pyridine-3-carboxylic acid. (0.88 g, 2.6 mmol).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, lOu, C18, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH 3 CN / 95% H 2 O / 10 mM ammonium acetate and solvent B was 5% H 2 0 / 95% CH 3 CN / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 300(MH + ).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, lOu, CI 8, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH 3 CN / 95% H 2 0 / 10 mM ammonium acetate and solvent B was 5% H 2 0 / 95% CH 3 CN / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 418 (MH + ).
  • LCMS retention time: 1.830 min.
  • LC data was recorded on a Shimadzu LC-1 OAS liquid chromatograph equipped with a Phenomenex-Luna, lOu, C18, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 390 (MH + ).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, lOu, CI 8, 4.6 x 50 mm column using a SPD- 10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10%> CH 3 OH / 90%> H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 507 (MH + ).
  • 2-(4-fluorophenyl)-N-methyl-5-(3-(l- phenylcyclopropylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide 2- (4-fluorophenyl)-N-methyl-5 -(3 -( 1 - phenylcyclopropylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[l,5-a]pyridin-5- yl)benzoic acid (0.070 g, 0.14 mmol) and 1-phenylcyclopropanamine hydrochloride (0.040 g, 0.20 mmol).
  • 2-(4-fluorophenyl)-N-methyl-5-(3-(l- phenylcyclobutylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide 2- (4-fluorophenyl)-N-methyl-5-(3-(l-phenylcyclobutylcarbamoyl)phenyl)pyrazolo[l,5- a]pyridine-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3- (methylcarbamoyl)pyrazolo[l,5-a]pyridin-5-yl)benzoic acid (0.070 g, 0.14 mmol) and 1 -phenylcyclobutanamine hydrochloride (0.040 g, 0.20 mmol).
  • LCMS retention time: 3.225 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, lOu, CI 8, 4.6 x 30 mm column using a SPD- 10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10%> CH 3 OH / 90%> H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 519 (MH + ).
  • 5-(3-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylpyrazolo[l,5- a]pyridine-3-carboxamide 5-(3-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)- N-methylpyrazolo[l,5-a]pyridine-3-carboxamide was prepared from 3-(2-(4- fluorophenyl)-3-(methylcarbamoyl) pyrazolo[l,5-a]pyridin-5-yl)benzoic acid (0.10 g, 0.20 mmol) and 2-methylpropan-2-amine (0.020 g, 0.30 mmol).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, lOu, CI 8, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 445 (MH + ).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% C3 ⁇ 4CN / 95% 3 ⁇ 40 / 10 mM ammonium acetate and solvent B was 5%> H 2 0 / 95%> CH 3 CN / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 201(MH + ).
  • N-(4-(benzyloxy)pyridin-3-yl)methanesulfonamide To a solution containing 4- (benzyloxy)pyridin-3 -amine (6.2 g, 15.8 mmol), triethylamine (1 1 mL, 79 mmol), and dichloromethane (163 mL) was added methanesufonylchloride (1.2 mL, 15.8 mmol) in dichloromethane (100 mL) drop wise over 90 min. The solution was maintained at room temperature for 6h and concentrated to afford N-(4- (benzyloxy)pyridin-3-yl)methanesulfonamide which was used without further purification.
  • LCMS retention time: 1.305 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters -Xterra, 5 micron, CI 8, 4.6 x 30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH 3 CN / 95% H 2 0 / 10 mM ammonium acetate and solvent B was 5% H 2 0 / 95% CH 3 CN / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 279 (MH + ).
  • N-(4-(benzyloxy)pyridin-3-yl)-N-(2-(tert-butyldimethylsilyloxy)ethyl) methanesulfonamide N-(4-(benzyloxy)pyridin-3 -yl)-N-(2-(tert- butyldimethylsilyloxy)ethyl) methanesulfonamide was prepared from N-(4-
  • Methyl 6-(N-(2- (tert-butyldimethylsilyloxy)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-5- hydroxypyrazolo [l,5-a]pyridine-3-carboxylate was prepared from -(4- (benzyloxy)pyridin-3-yl)-N-(2-(tert-butyldimethylsilyloxy)ethyl)
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5 micron, C18, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 538 (MH + ).
  • Methyl 6-(N-(2-(tert-butyldimethylsilyloxy)ethyl)methylsulfonamido)- 2-(4-fluorophenyl)-5-(trifluoromethylsulfonyloxy)pyrazolo[l,5-a]pyridine-3- carboxylate was prepared from Methyl 2-(4-fluorophenyl)-5-hydroxy-6-(N-(2- hydroxyethyl) methylsulfonamido) pyrazolo[l,5-a]pyridine-3-carboxylate (0.15 g, 0.29 mmol).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5 micron, C18, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 670 (MH + ).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5 micron, C18, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90%) CH 3 CN / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 528 (MH + ).
  • Methyl 2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)- 5-(3-(l-(pyridin-2-yl)cyclopropylcarbamoyl) phenyl)pyrazolo[l,5-a]pyridine-3- carboxylate was prepared from 3-(2-(4-fluorophenyl)-6-(N-(2- hydroxyethyl)methylsulfonamido)-3-(methoxycarbonyl)pyrazolo[l,5-a]pyridin-5- yl)benzoic acid (0.05 g, 0.10 mmol) and l-(pyridin-2-yl)cyclopropanamine dihydrochloride (0.03 g, 0.15 mmol).
  • LCMS retention time: 1.473 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters- Sunfire, 5 micron, CI 8, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 254 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 644 (MH + ).
  • LCMS retention time: 1.220 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters- Sunfire, 5 micron, CI 8, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 630 (MH + ).
  • Ethyl 6-bromo-2-(4-fluorophenyl)imidazo[l,2-a]pyridine-3-carboxylate Ethyl 3- (4-fluorophenyl)-3-oxopropanoate (2.6 g, 12 mmol) was dissolved into DCM (32 mL), cooled to 0 °C and treated with tetra-n-butylammonium tribromide (6.75 g, 14.0 mmol). The reaction mixture was stirred at 0 °C for lh, rt for lh and then washed with sat NaHC0 3 (aq) (2 x 50 mL), dried (MgS0 4 ), filtered and concentrated.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% TFA and solvent B was 10% H20 / 90% acetonitrile / 0.1% TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • the reaction was sealed and heated at 100 °C overnight.
  • the reaction solution was cooled to rt, filter to remove solids, diluted with water ( ⁇ 10 mL) and acidified with IN HCl (aq) (1.5 mL, 1.5 mmmol).
  • the white precipitate that formed was collected by filtration, washed with water and dried to yield 3-(2-(4-fluorophenyl)-3- (methylcarbamoyl)imidazo[l,2-a]pyridin-6-yl)benzoic acid (174 mg, 0.335 mmol, 78% yield) as a white solid.
  • LC data was recorded on a Shimadzu LC- 10AS liquid chromatograph equipped with a Phenomenex-Luna lOu CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% TFA and solvent B was 10% H20 / 90% acetonitrile / 0.1% TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu CI 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% TFA and solvent B was 10% H20 / 90% acetonitrile / 0.1% TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.
  • 1,4- Dioxane (1.25 mL) and water (0.25 mL) were added, the vial was capped, and the reaction was heated in an oil bath to 90 °C. After 7 h, the reaction was cooled to r.t. and diluted with water. 1 mL of 1 N HC1 was added and a ppt. formed. The suspension was extracted with EtOAc (+ MeOH to aid dissolution), and the organic phase was washed with brine, dried over Na 2 S0 4 , filtered, and concentrated to give a tan solid. This was purified by prep HPLC, and concentrated to give a white solid, (12 mg, 18% yield).
  • Methyl phenylpropiolate 1000 mg, 6.24 mmol was added in dimethylformamide (9 mL). Potassium carbonate (2504 mg, 18.12 mmol) was added. Reaction slowly turned dark green. After stirring at room temp for 2 hours, the reaction was poured into diethyl ether (300 mL and extracted 8x 25 mL water. The solvent was removed from the organic portion by rotory evaporation. The crude product was dissolved in a minimum amount of dichloromethane and charged to a 90g "Single Sep" silica gel cartridge and eluted with 0 to 40% ethyl acetate in hexanes over 1000 mL.
  • Methyl-6-iodo-2-phenylpyrazolo[l,5-a]pyridine-3-carboxylate 250 mg, 0.661 mmol was dissolve in aqueous LiOH(2N, l mL), methanol(2mL) and tetrahydrofuran(7 mL). This solution was stirred overnight at 45°C. After 24 hours, 2 mL 2M LiOH and 2 mL methanol were added. Heated at 55°C overnight.
  • 6- Iodo-N-methyl-2-phenylpyrazolo[l,5-a]pyridine-3-carboxamide To a 250 mL round-bottomed flask equiped with a magnetic stir bar was charged 6-iodo-2- phenylpyrazolo[l,5-a]pyridine-3-carboxylic acid (200 mg, 0.549 mmol), 1-Hydroxy-
  • 6-(2-Methoxyphenyl)-N-methyl-2-phenylpyrazolo[l,5-a]pyridine-3- carboxamide To a microwave vial equipped with a magnetic stir bar was charged 2-methoxyphenylboronic acid (12.09 mg, 0.080 mmol), 6-iodo-N-methyl-2- phenylpyrazolo[l,5-a]pyridine-3-carboxamide (15 mg, 0.040 mmol), sodium carbonate (7.38 mg, 0.070 mmol), palladium(II) acetate (0.893 mg, 3.98 ⁇ ) and dimethylforamide (1.0 mL). This mixture was placed under an argon atmosphere and heated at 150°C for 10 minutes.
  • Methyl 2-(4-fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylate To a cooled solution (-78 C, dry ice, acetone) containing 2-(4-fluorophenyl)-3-iodo-5- methoxybenzo[b]thiophene (1.0 g, 2.6 mmol,) and THF (26 mL) was added n- butyllithium (2.0 mL, 1.0 M THF) over 5 min. The solution was maintained at -78 C for lh. Methylchloroformate (0.80 mL, 10.4 mmol) was then added quickly in a steady stream via syringe.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% C3 ⁇ 4CN / 95% 3 ⁇ 40 / 10 mM ammonium acetate and solvent B was 5%> H 2 0 / 95%> CH 3 CN / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 317(MH + ).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, CI 8, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% C3 ⁇ 4CN / 95% 3 ⁇ 40 / 10 mM ammonium acetate and solvent B was 5%> H 2 0 / 95%> CH 3 CN / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 303(MH + ).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, CI 8, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% C3 ⁇ 4CN / 95% H 2 O / 10 mM ammonium acetate and solvent B was 5% H 2 0 / 95% CH 3 CN / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 316 (MH + ).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, CI 8, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% C3 ⁇ 4CN / 95% 3 ⁇ 40 / 10 mM ammonium acetate and solvent B was 5% 3 ⁇ 40 / 95% C3 ⁇ 4CN / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 302 (MH + ).
  • Phenylbis(trifluoromethane)sulfonamide (0.50 g, 1.4 mmol), triethylamine (0.64 mL, 4.6 mmol) and dichloromethane (9.2 mL) was maintained at room temperature for 16 h. The solution was further diluted with dichloromethane (30 mL), washed with saturated, aqueous sodium bicarbonate (20 mL), washed with water (10 mL), dried over MgS04, filtered and concentrated.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 406 (MH + ).
  • LCMS retention time: 3.305 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 523 (MH + ).
  • 2-(4-fluorophenyl)-N-methyl-5-(3-(l- phenylcyclopropylcarbamoyl)phenyl)benzo[b]thiophene-3-carboxamide 2-(4- fluorophenyl)-N-methyl-5-(3 -( 1 - phenylcyclopropylcarbamoyl)phenyl)benzo[b]thiophene-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5- yl)benzoic acid (0.075 g, 0.154 mmol) and 1-phenylcyclopropanamine hydrochloride (0.038 g, 0.22 mmol).
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10%> CH 3 OH / 90%> H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 521 (MH + ).
  • 2-(4-fluorophenyl)-N-methyl-5-(3-(l- phenylcyclobutylcarbamoyl)phenyl)benzo[b]thiophene-3-carboxamide 2-(4- fluorophenyl)-N-methyl-5-(3 -( 1 - phenylcyclobutylcarbamoyl)phenyl)benzo[b]thiophene-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl)benzoic acid (0.075 g, 0.15 mmol) and 1-phenylcyclobutanamine hydrochloride (0.041 g, 0.22 mmol).
  • LCMS retention time: 3.370 min.
  • LC data was recorded on a Shimadzu LC- 10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, CI 8, 4.6 x 30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 535 (MH + ).
  • 5-(3-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N- methylbenzo[b]thiophene-3-carboxamide 5-(3-(tert-butylcarbamoyl)phenyl)-2-(4- fluorophenyl)-N-methylbenzo[b]thiophene-3-carboxamide was prepared from 3-(2- (4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl)benzoic acid (0.075 g, 0.15 mmol) and 2-methylpropan-2-amine (0.016 g, 0.22 mmol).
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 461 (MH + ).
  • LCMS retention time 1.800 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire CI 8, 5 micron, C18, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90%) CH 3 CN / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 638 (M a + ).
  • 6- ( -(2-hydroxyethyl)methylsulfonamido)-N-methylpyrazolo[l,5-a]pyridine-3- carboxamide was prepared from 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(2- hydroxyethyl) methylsulfonamido)pyrazolo[l,5-a]pyridine-3-carboxylic acid (0.013 g, 0.030 mmol) and methylamine hydrochloride (0.008 g, 0.12 mmol).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire CI 8, 5 micron, CI 8, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 468.8 (MNa + ).
  • 6-CN-ethylmethylsulfonamido)-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan- 2-ylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide was prepared from 6- ( -ethylmethylsulfonamido)-2-(4-fluorophenyl)-5-(3-(2-phenylpropan-2- ylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxylic acid (0.030 g, 0.049 mmol) and methylamine hydrochloride (0.014 g, 0.19 mmol).
  • LCMS retention time 2.213 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire CI 8, 5 micron, CI 8, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% C3 ⁇ 4CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 niM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 628 (MH + ).
  • 2-(4-fluorophenyl)- N-methyl-6-(methylsulfonamido)-5-(3-(2-phenylpropan-2- ylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide was prepared from 2-(4- fluorophenyl)-6-(methylsulfonamido)-5-(3-(2-phenylpropan-2- ylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxylic acid (0.088 g, 0.090 mmol) and methylamine hydrochloride (0.024 g, 0.36 mmol).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire C18, 5 micron, C18, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 mM TFA.
  • LCMS retention time 2.352 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire CI 8, 5 micron, CI 8, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 niM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 654 (MH + ).
  • 6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-N-methyl-5- phenylpyrazolo[l,5-a]pyridine-3-carboxamide 6-(N-ethylmethylsulfonamido)-2- (4-fluorophenyl)-N-methyl-5-phenylpyrazolo[l,5-a]pyridine-3-carboxamide was prepared from 6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-5- phenylpyrazolo[l,5-a] pyridine-3-carboxylic acid (0.019 g, 0.042 mmol) and methylamine hydrochloride (0.011 g, 0.16 mmol).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Xterra, 7 micron, CI 8, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% methanol / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% methanol/ 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 466.9 (MH + ).
  • 5-cyclohexyl-6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-N- methylpyrazolo[l,5-a]pyridine-3-carboxamide 5-cyclohexyl-6-(N- ethylmethylsulfonamido)-2-(4-fluorophenyl)-N-methylpyrazolo[l,5-a]pyridine-3- carboxamide was prepared from 5-cyclohexyl-6-( -ethylmethylsulfonamido)-2-(4- fluorophenyl)pyrazolo[l,5-a]pyridine-3-carboxylic acid (0.018 g, 0.039 mmol) and methylamine hydrochloride (0.011 g, 0.16 mmol).
  • LCMS retention time 1.577 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Xterra, 7 micron, CI 8, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% methanol / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% methanol/ 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 473 (MH + ).
  • 5-cyclopentyl-6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-N- methylpyrazolo[l,5-a]pyridine-3-carboxamide 5-cyclopentyl-6-(N- ethylmethylsulfonamido)-2-(4-fluorophenyl)-N-methylpyrazolo[l,5-a]pyridine-3- carboxamide was prepared from 5-cyclohexyl-6-( -ethylmethylsulfonamido)-2-(4- fluorophenyl)pyrazolo[l,5-a]pyridine-3-carboxylic acid (0.015 g, 0.034 mmol) and methylamine hydrochloride (0.009 g, 0.13 mmol).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Xterra, 7 micron, C18, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% methanol / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% methanol/ 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 430.8 (MH + ).
  • 6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-5- (5-(l-(4-fluorophenyl) cyclopropylcarbamoyl)-2-methylphenyl)-N- methylpyrazolo[l,5-a]pyridine-3-carboxamide was prepared from 3-(6-(N- ethylmethylsulfonamido)-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[l,5- a]pyridin-5-yl)-4-methylbenzoic acid (0.024 g, 0.046 mmol) and l-(4- fluorophenyl)cyclopropanamine hydrochloride (0.013 g, 0.069 mmol).
  • LCMS retention time 1.920 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% C3 ⁇ 4CN / 95% 3 ⁇ 40 / 10 mM ammonium acetate and solvent B was 5% H 2 0 / 95% CH 3 CN / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 658 (MH + ).
  • 2-(4- fluorophenyl)-5-(5-(l-(4-fluorophenyl)cyclopropylcarbamoyl)-2-methylphenyl)-N- methylpyrazolo[l,5-a]pyridine-3-carboxamide was prepared from 3-(2-(4- fluorophenyl)-3-(methylcarbamoyl)pyrazolo[l,5-a]pyridin-5-yl)-4-methylbenzoic acid (0.016 g, 0.040 mmol) and 1 -(4-fluorophenyl)cyclopropanamine hydrochloride (0.011 g, 0.059 mmol).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, CI 8, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% methanol / 90% water / 10 mM TFA and solvent B was 10% water / 90% methanol / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 537 (MH + ).
  • LCMS retention time 1.870 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, CI 8, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% methanol / 90% water / 10 mM TFA and solvent B was 10% water / 90% methanol / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 533 (MH + ).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire C18, 5 micron, C18, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 533 (MH + ).
  • tert-butyl 5-chloro-6-fluoro-2-(4-fluorophenyl)pyrazolo[l,5-a]pyridine-3- carbonyl(methyl)carbamate and tert-butyl 5-chloro-4-fluoro-2-(4- fluorophenyl)pyrazolo[l,5-a]pyridine-3-carbonyl(methyl)carbamate were prepared as a residue containing a mixture of regioisomers starting from 4-chloro-3- fluoropyridine (2.0 g, 15.2 mmol). Isolation on silica gel (0-80% ethyl
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire C18, 5 micron, C18, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 mM TFA.
  • LCMS retention time 2.625 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire CI 8, 5 micron, CI 8, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10%
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 522 (MH + ).
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 CN / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 CN / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 444 (M a + ).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Xbridge, 5 micron, CI 8, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% CH 3 CN / 95% 3 ⁇ 40 / 10 mM ammonium acetate and solvent B was 5%> H 2 0 / 95%> CH 3 CN / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 537 (MH + ).
  • 6-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(l-phenylcyclopropyl carbamoyl) phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide was prepared from 3-(6- fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[l,5-a]pyridin-5-yl)-4- methylbenzoic acid (0.024 g, 0.059 mmol) and 1-phenylcyclopropanamine hydrochloride (0.015 g, 0.089 mmol).
  • LCMS retention time 2.535 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, CI 8, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% methanol / 90% water / 10 mM TFA and solvent B was 10% water / 90% methanol / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 537 (MH + ).
  • LC data was recorded on a Shimadzu LC- 10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 555 (MH + ).
  • LCMS retention time 1.828 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, CI 8, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 556 (MH + ).
  • LCMS retention time 2.137 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, CI 8, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 561 (MH + ).
  • LCMS retention time 2.533 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 573 (MH + ).
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90%) CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 573 (MH + ).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, CI 8, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 505 (MH + ).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, CI 8, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 585 (MH + ).
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0%) solvent B to 0%> solvent A / 100%> solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 531 (MH + ).
  • LCMS retention time 2.502 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C 18, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% 3 ⁇ 40 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 533 (MH + ).
  • LCMS retention time 2.480 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90%) CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 585 (MH + ).
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 585 (MH + ).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, CI 8, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 569 (MH + ).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, CI 8, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10%> CH 3 OH / 90%> H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 539 (MH + ).
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90%) CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 460 (M a + ).
  • the solution thus obtained was cooled to 0°C (ice bath) and added dropwise with stirring to a pre- cooled solution (-50°C, dry ice, acetone) containing tert-butyl 5,7-dichloro-2-(4- fluorophenyl)pyrazolo[l,5-a]pyridine-3-carbonyl (methyl) carbamate and THF (0.608 mL, 0.38 M).
  • the solution thus obtained was removed from cooling and allowed to proceed for 18h.
  • the solution was poured into water (25 mL). The aqueous portion was then extracted with ethyl acetate (2 x 25 mL).
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 422 (MH + ).
  • the mixture was stirred at 95°C for 18 h.
  • the mixture was cooled to room temperature, filtered to remove solids and adjusted to below pH 4 with 1 N aqueous hydrochloric acid (2.0 mL). Water was added (10 mL) and the aqueous portion was extracted with ethyl acetate (2 x 15 mL). The combined organic portions were washed with brine (20 mL) and dried over magnesium sulfate.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 522 (MH + ).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH 3 OH / 90% H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 637 (MH + ).
  • LCMS retention time 1.873 min.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, CI 8, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.
  • the elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10%> CH 3 OH / 90%> H 2 0 / 10 mM TFA and solvent B was 10% H 2 0 / 90% CH 3 OH / 10 mM TFA.
  • MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 538 (MH + ). 5-bromo-2-(4-fluorophenyl)furo [2,3-b] yridine.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% acetonitrile / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid 3- Carboxyphenylboronic acid (700 mg, 4.22 mmol), 5-bromo-2-(4- fluorophenyl)furo[2,3-b]pyridine (750 mg, 2.57 mmol), Pd(Ph3P)4 (30 mg, 0.026 mmol), and Cs2C03 (1.25g, 3.84 mmol) were combined in dioxane (20 mL) and water (4 mL). The mixture was evacuated/backfilled with nitrogen (3x). The reaction was heated to 95 °C under N2 (g) overnight. The mixture was partitioned between EtOAc and 1 N HC1.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • the material was resubjected to the reaction conditions (80 mg of NBS in 3 mL THF/0.5 mL DMF). After 3 h, the reaction was quenched by the addition of 10% Na2S203, and the solution was acidified with 0.1 N HC1. The volatiles were removed and the resulting off-white precipitate was collected by filtration, rinsed with water and Et20, and air-dried to afford the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (140 mg, 53%o yield) as an off-white powder consistent by LCMS and NMR.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 1 Preparation of 6-bromo-2-iodopyridin-3-ol. N-iodosuccinimide (6.47 g, 28.7 mmol) was added to a stirring solution of 6-bromopyridin-3-ol (5 g, 28.7 mmol) in MeOH (144 mL) at 45 °C. It was allowed to stir for 3 hours. The mixture was concentrated and triturated with Et20. The precipitate was discarded and the filtrate was concentrated and triturated with dichloromethane to give the expected product, 1
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10%> H20 / 90%> acetonitrile / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode. Step 2: Preparation of 6-bromo-2-iodopyridin-3-yl acetate.
  • 6-bromo-2-iodopyridin- 3-ol 150 mg, 0.500 mmol was added to acetic anhydride (2.4 mL, 25 mmol) at 130 °C. It was allowed to stir for 30 min then concentrated and chased with toluene to give the expected product 6-bromo-2-iodopyridin-3-yl acetate (171 mg, 0.500 mmol, 100 % yield) by NMR.
  • Step 3 Preparation of 6-bromo-2-((4-fluorophenyl)ethynyl)pyridin-3-yl acetate.
  • 6- bromo-2-iodopyridin-3-yl acetate (3.50 g, 10.24 mmol)
  • 1 -ethynyl-4-fluorobenzene (1.11 g, 9.21 mmol)
  • copper (I) iodide (1 17 mg, 0.614 mmol)
  • trans- dichlorobis(triphenylphosphine)palladium (II) (359 mg, 0.512 mmol) were combined and evacuated/backfilled with N2 (3x) then diluted with triethylamine (100 ml) and heated to 85 °C for 2 hours.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100%> solvent A / 0%> solvent B to 0%> solvent A / 100%> solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% acetonitrile / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 4 Preparation of methyl 5-bromo-2-(4-fluorophenyl)furo[3,2-b]pyridine-3- carboxylate.
  • Sodium acetate (15 mg, 0.18 mmol), K2C03 (25 mg, 0.18 mmol), copper(II) chloride dihydrate (46 mg, 0.27 mmol), palladium(II) chloride (2.0 mg, 0.012 mmol) was added to a stirring solution of 6-bromo-2-((4- fluorophenyl)ethynyl)pyridin-3-yl acetate (30 mg, 0.090 mmol) in MeOH (2 mL) at room temperature in a Parr Bomb.
  • the vessel was charged with 300 PSI of CO (g) and allowed to stir at room temperature overnight.
  • the mixture was diluted with EtOAc and washed with sat NaHC03, and sat NaCl.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% acetonitrile / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode. Step 5: Preparation of 5-bromo-2-(4-fluorophenyl)-N-methylfuro[3,2-b]pyridine-3- carboxamide.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% acetonitrile / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 1 Preparation of 2-(benzyloxy)-5- (methoxymethoxy) pyridine. NaH (1.2 g, 29.8 mmol) was added to a stirring solution of 6-(benzyloxy) pyridin-3-ol (5.0 g, 24.85 mmol) in DMF (100 mL) at 0°C. Then it was allowed to warm to room temperature and stir for 25 min then was treated with MOM-C1 (2.55 mL, 28.6 mmol) and the reaction was allowed to stir for 2 hrs. The mixture was quenched with H20 then concentrated about 80% then diluted with EtOAc and washed with H20, and sat NaCl. The organic phase was dried over Na2S04, filtered and concentrated was purified on silica gel (Biotage,
  • LC-MS retention time 1.88 min; m/z (MH+): 246.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6x50mm column using a SPD- 10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% acetonitrile / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 2 Preparation of 2-(benzyloxy)-4-iodo-5-(methoxymethoxy) pyridine.
  • tBuLi 27 mL, 46.2 mmol
  • 2-(benzyloxy)-5- (methoxymethoxy)pyridine 5.4 g, 22.06 mmol
  • THF 110 mL
  • iodine 8.4 g, 33.1 mmol
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% acetonitrile / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 3 Preparation of 2-(benzyloxy)-4-((4-fluorophenyl)ethynyl)-5- (methoxymethoxy)pyridine.
  • 2-(benzyloxy)-4-iodo-5-(methoxymethoxy)pyridine (3.0 g, 8.08 mmol)
  • copper (I) iodide (92 mg, 0.485 mmol)
  • PdC12(PPh3)2 (284 mg, 0.404 mmol)
  • l-ethynyl-4-fluorobenzene (1.07 g, 8.89 mmol) were combined in dioxane (40 mL) and TEA (40 mL), degassed and stirred at 80 °C for 1.5 hrs.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% acetonitrile / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 4 Preparation of 6-(benzyloxy)-4-((4-fluorophenyl)ethynyl)pyridin-3-ol.
  • Trifluoroacetic acid (0.95 mL, 12.4 mmol) was added to a stirring solution of 2-
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% acetonitrile / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 5 Preparation of methyl 5-(benzyloxy)-2-(4-fluorophenyl)furo[2,3-c]pyridine- 3-carboxylate.
  • palladium (II) chloride (0.205 g, 1.15 mmol) was added to a stirring solution of 6-(benzyloxy)-4-((4- fluorophenyl)ethynyl)pyridin-3-ol (2.22 g, 6.95 mmol) in MeOH (150 mL) at room temperature in a Parr Bomb.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10%) H20 / 90%> acetonitrile / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 6 Preparation of 5-(benzyloxy)-2-(4-fluorophenyl)furo[2,3-c]pyridine-3- carboxylic acid.
  • NaOH 27.8 mL, 27.8 mmol, 1M aq.
  • the mixture was diluted with ethyl acetate and washed with 1M HC1, and sat NaCl.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% acetonitrile / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 7 Preparation of 5-(benzyloxy)-2-(4-fluorophenyl)-N-methylfuro[2,3- c]pyridine-3-carboxamide.
  • Methanamine (3.1 mL, 6.2 mmol, 2M in THF) was added to a stirring solution of DIEA (646 ⁇ , 3.70 mmol), HATU (563 mg, 1.48 mmol), 5- (benzyloxy)-2-(4-fluorophenyl)furo[2,3-c]pyridine-3-carboxylic acid (448 mg, 1.23 mmol) in DMF (12 mL) at room temperature.
  • the mixture concentrated then diluted with EtOAc and washed with sat NaCl.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% acetonitrile / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 8 Preparation of 2-(4-fluorophenyl)-5-hydroxy-N-methylfuro[2,3-c]pyridine-3- carboxamide.
  • Triflic anhydride (Tf20, 319 ⁇ ⁇ , 1.89 mmol) was added to a stirring solution of 2-(4-fluorophenyl)-5-hydroxy-N-methylfuro[2,3-c]pyridine-
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10%> H20 / 90%> acetonitrile / 0.1%> trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 1 Preparation of 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-N-(2-phenylpropan-2- yl)benzamide.
  • DIEA (210 ⁇ , 1.20 mmol) was added to a stirring solution of HATU (228 mg, 0.600 mmol), 2-phenylpropan-2-amine (69.1 ⁇ , 0.480 mmol), 3-(3-bromo- 2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (165 mg, 0.400 mmol) in DMF (4 mL) at room temperature. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with 1M HC1, and sat NaCl.
  • LC-MS retention time 1.97 min; m/z (MH+): 529, 531.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu CI 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 2 Preparation of 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)-N-(2- phenylpropan-2-yl)benzamide.
  • Pd(Ph3P)4 (4.4 mg, 3.8 ⁇ ) was added to a stirring solution of 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-N-(2- phenylpropan-2-yl)benzamide (20 mg, 0.038 mmol), trimethylboroxine (1 1 ⁇ , 0.076 mmol), and Na2C03 (12.0 mg, 0.1 1 mmol) in DMF (1.4 mL) and Water (.14 mL) at room temperature.
  • LC- MS retention time 1.87 min; m/z (MH+): 465.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 3 Preparation of 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)-N-(2- phenylpropan-2-yl)benzamide.
  • AIBN 1.0 mg, 6.1 ⁇
  • NBS 4.6 mg, 0.026 mmol
  • 3-(2-(4-fluorophenyl)-3-methylfuro[2,3- b]pyridin-5-yl)-N-(2-phenylpropan-2-yl)benzamide 11 mg, 0.024 mmol) in CC14 (1 mL).
  • the mixture was heated to 76 °C and allowed to stir for 2 hours.
  • the reaction was concentrated and diluted with DMSO (1 mL) and treated with NMO (3.4 mg, 0.028 mmol) and subjected to microwave irradiation (150°C) for 5 min.
  • the reaction was purified by preparative reverse phase HPLC on a CI 8 column using a suitably buffered H 2 0/CH 3 CN gradient, and concentrated to give to give the expected product 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)-N-(2-phenylpropan-2- yl)benzamide (7.5 mg, 0.016 mmol, 66 % yield) consistent by LCMS and NMR.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0%> solvent B to 0%> solvent A / 100%> solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • Step 4 Preparation of 2-(4-fluorophenyl)-5-(3-(2-phenylpropan-2- ylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxylic acid.
  • Oxone 28 mg, 0.046 mmol
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 5 Preparation of the title compound, 2-(4-fluorophenyl)-N-methyl-5-(3-(2- phenylpropan-2-ylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxamide.
  • Methanamine (253 ⁇ , 0.506 mmol, 2M in THF) was added to a stirring solution of 2-(4-fluorophenyl)-5-(3-(2 ⁇ henylpropan-2-ylcarbamoyl)phenyl)furo[2,3-b]pyridine- 3-carboxylic acid (50 mg, 0.10 mmol), DIEA (53 ⁇ , 0.30 mmol), DMAP (1.2 mg, 10 ⁇ ), HATU (58 mg, 0.15 mmol) in DMF (1 mL) at room temperature.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu CI 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • DIEA (286 ⁇ ,, 1.64 mmol) was added to a stirring solution of HATU (31 1 mg, 0.819 mmol), 1-phenylcyclopropanamine hydrochloride (1 11 mg, 0.655 mmol), and 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5- yl)benzoic acid (225 mg, 0.546 mmol) in DMF (6 mL) at room temperature. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with 1M HC1, and sat NaCl.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100%> solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 2 Preparation of 3-(2-(4-fluorophenyl)-3-methylfuro[2,34o]pyridin-5-yl)-N-(l- phenylcyclopropyl)benzamide.
  • Pd(Ph3P)4 (16 mg, 0.014 mmol) was added to a stirring solution of 3-(3-bromo-2-(4-fluorophenyl)furo[2,34o]pyridin-5-yl)-N-(l- phenylcyclopropyl)benzamide (75 mg, 0.14 mmol), trimethylboroxine (40 ⁇ , 0.28 mmol), and Na2C03 (45 mg, 0.43 mmol) in DMF (1.3 mL) and Water (.13 mL) at room temperature.
  • LC-MS retention time 1.81 min; m/z (MH+): 463.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 3 Preparation of 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)-N-(l- phenylcyclopropyl)benzamide.
  • AIBN 6.5 mg, 0.040 mmol
  • NBS 26 mg, 0.15 mmol
  • 3-(2-(4-fluorophenyl)-3-methylfuro[2,3- b]pyridin-5-yl)-N-(l-phenylcyclopropyl)benzamide 61 mg, 0.13 mmol) in CC14 (20 ml). The mixture was heated to 76 °C and allowed to stir for 2 hours.
  • the reaction was concentrated and diluted with DMSO (1 mL) and treated with NMO (18.5 mg, 0.158 mmol) and subjected to MW irradiation (150°C) for 10 min.
  • the mixture was diluted with EtOAc and washed with 10% NaHS04 2x followed by H20 and Brine.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100%> solvent A / 0% solvent B to 0% solvent A / 100%> solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 4 Preparation of the title compound, 2-(4-fluorophenyl)-N-methyl-5-(3-(l- phenylcyclopropylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxamide.
  • AIBN 3.6 mg, 0.022 mmol
  • NBS 17 mg, 0.095 mmol
  • 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)-N-(l- phenylcyclopropyl)benzamide 35 mg, 0.073 mmol
  • CC14 10 mL
  • reaction was removed from the heat and allowed to stir for 2 min and treated with methanamine (0.184 mL, 0.367 mmol, 2M in THF). The reaction was allowed to stir for 1 hour and concentrated. The residue was diluted with EtOAc and washed with 10% sodium bisulfate, and sat NaCl.
  • LC-MS retention time 1.98 min; m/z (MH+): 506.
  • LC data was recorded on a Shimadzu LC- 10AS liquid chromatograph equipped with a Waters SunFire 5u CI 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% acetonitrile / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 1 Preparation of methyl 3-(3-bromo-2-(4- fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoate.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100%> solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 2 Preparation of methyl 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5- yl)benzoate.
  • 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (0.236 mL, 1.69 mmol) was added to a stirring solution of methyl 3-(3-bromo-2-(4-fluorophenyl)furo[2,3- b]pyridin-5-yl)benzoate (360 mg, 0.845 mmol), sodium carbonate (269 mg, 2.53 mmol), Pd(Ph3P)4 (98 mg, 0.084 mmol) in DMF (10 mL) and Water (1.0 mL).
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 3 Preparation of methyl 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5- yl)benzoate.
  • AIBN (22.2 mg, 0.135 mmol) was added to a stirring solution of NBS (88 mg, 0.49 mmol) and methyl 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5- yl)benzoate (163 mg, 0.451 mmol) in CC14 (40 mL) and was heated to 76 °C. The mixture was allowed to stir for 2 hours.
  • the reaction was concentrated and diluted with DMSO (1 mL) and treated with NMO (63 mg, 0.54 mmol) and subjected to MW irradiation (150°C) for 10 min.
  • the mixture was diluted with EtOAc and washed with 10% NaHS04 2x followed by H20 and Brine.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 4 Preparation of methyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3- b]pyridin-5-yl)benzoate.
  • AIBN 4 mg, 0.028 mmol
  • NBS 21.6 mg, 0.121 mmol
  • methyl 3-(2-(4-fluorophenyl)-3- formylfuro[2,3-b]pyridin-5-yl)benzoate 35 mg, 0.093 mmol
  • CC14 5 niL
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 5 Preparation of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin- 5-yl)benzoic acid.
  • NaOH 0.297 mL, 0.297 mmol, 1M aq.
  • MeOH 2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5- yl)benzoate (24 mg, 0.059 mmol) in MeOH (2 mL) at room temperature. It was allowed to stir overnight. The mixture was diluted with EtOAc and washed with 1M HC1, and sat NaCl.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100%> solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 6 Preparation of the title compound, 5-(3-(tert-butylcarbamoyl)phenyl)-2-(4- fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide.
  • LC-MS retention time 1.68 min; m/z (MH+): 446.
  • LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna lOu CI 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220nM.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH / 90% H20 / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 1 Preparation of 4-chloro-3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid.
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100%> solvent A / 0%> solvent B to 0%> solvent A / 100%> solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 2 Preparation of 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4- chlorobenzoic acid.
  • NBS 29.0 mg, 0.163 mmol
  • 4-chloro-3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid 50 mg, 0.136 mmol
  • THF 4.5 mL
  • the elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H20 / 10 mM ammonium acetate and solvent B was 5% H20 / 95% acetonitrile / 10 mM ammonium acetate.
  • MS data was determined using a Micromass Platform for LC in electrospray mode.
  • Step 3 Preparation of 4-chloro-3-(2-(4-fluorophenyl)-3-(methoxycarbonyl)furo[2,3- b]pyridin-5-yl)benzoic acid.
  • l,3-bis(diphenylphosphino)propane 28 mg, 0.067 mmol
  • palladium(II) acetate 7.5 mg, 0.034 mmol
  • 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-chlorobenzoic acid 75 mg, 0.17 mmol
  • MeOH 0.6 mL
  • DMSO 1.1 mL
  • Step 4 5-(2-chloro-5-(l -(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4- fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide.
  • DIEA (142 ⁇ ,, 0.810 mmol) was added to a stirring solution of l-(pyridin-2-yl)cyclopropanamine dihydrochloride (84 mg, 0.405 mmol), 4-chloro-3-(2-(4-fluorophenyl)-3- (methoxycarbonyl)furo[2,3-b]pyridin-5-yl)benzoic acid (115 mg, 0.270 mmol) and HATU (154 mg, 0.405 mmol) in DMF (2.7 mL) at room temperature. It was allowed to stir for 1 hour. The mixture was diluted with ethyl acetate and washed with sat NaHC03, and sat NaCl.

Landscapes

  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne dix composés spécifiques ayant une structure de base pyrazolo[1,5-a]pyridine, y compris leurs sels, ainsi que des compositions et des procédés d'utilisation des composés. Les composés sont actifs contre le virus de l'hépatite C (HCV) et peuvent être utilisés dans le traitement de patients infectés par le HCV.
PCT/US2010/026786 2010-03-10 2010-03-10 Composés destinés au traitement de l'hépatite c WO2011112186A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
PCT/US2010/026786 WO2011112186A1 (fr) 2010-03-10 2010-03-10 Composés destinés au traitement de l'hépatite c
JP2012557016A JP5572725B2 (ja) 2010-03-10 2010-03-10 Ｃ型肝炎の処置のための化合物
EP10708084.8A EP2545050B1 (fr) 2010-03-10 2010-03-10 Composés destinés au traitement de l'hépatite c
CN2010800667299A CN102906089A (zh) 2010-03-10 2010-03-10 用于治疗丙型肝炎的化合物

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2010/026786 WO2011112186A1 (fr) 2010-03-10 2010-03-10 Composés destinés au traitement de l'hépatite c

Publications (1)

Publication Number Publication Date
WO2011112186A1 true WO2011112186A1 (fr) 2011-09-15

Family

ID=42985432

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/026786 WO2011112186A1 (fr) 2010-03-10 2010-03-10 Composés destinés au traitement de l'hépatite c

Country Status (4)

Country Link
EP (1) EP2545050B1 (fr)
JP (1) JP5572725B2 (fr)
CN (1) CN102906089A (fr)
WO (1) WO2011112186A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012051659A1 (fr) * 2010-10-20 2012-04-26 Biota Scientific Management Pty Ltd Inhibiteurs d'une polymérase virale
US8614207B2 (en) 2010-10-26 2013-12-24 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis C virus
US8785478B2 (en) 2012-04-11 2014-07-22 Biota Scientific Management Pty Ltd. Viral polymerase inhibitors
WO2014164968A1 (fr) * 2013-03-13 2014-10-09 Bristol-Myers Squibb Company Nouveaux composés pour le traitement de l'hépatite c
WO2015143255A1 (fr) * 2014-03-21 2015-09-24 Bristol-Myers Squibb Company Composés azabenzofurane contenant un groupe cyano pour le traitement de l'hépatite c
WO2015169776A1 (fr) 2014-05-08 2015-11-12 Bayer Cropscience Ag Sulfonamides de pyrazolopyridine en tant que nématicides
WO2016022513A1 (fr) * 2014-08-05 2016-02-11 Bristol-Myers Squibb Company Composés furopyridine pour le traitement de l'hépatite c
US10392413B2 (en) 2015-12-18 2019-08-27 Ardelyx, Inc. Substituted 4-phenyl pyridine compounds as non-systemic TGR5 agonists
WO2022182861A1 (fr) * 2021-02-26 2022-09-01 Enanta Pharmaceuticals, Inc. Composés hétérocycliques antiviraux
US11572367B2 (en) 2019-10-04 2023-02-07 Enanta Pharmaceuticals, Inc. Antiviral heterocyclic compounds
WO2023227698A1 (fr) * 2022-05-25 2023-11-30 Katholieke Universiteit Leuven Nouveaux dérivés pour le traitement de troubles médiés par trpm3
US11912695B2 (en) 2019-03-18 2024-02-27 Enanta Pharmaceuticals, Inc. Benzodiazepine derivatives as RSV inhibitors
US11945824B2 (en) 2020-10-19 2024-04-02 Enanta Pharmaceuticals, Inc. Heterocyclic compounds as anti-viral agents
US11952389B2 (en) 2015-07-22 2024-04-09 Enanta Pharmaceuticals, Inc. Benzodiazepine derivatives as RSV inhibitors
US12006326B2 (en) 2022-08-24 2024-06-11 Enanta Pharmaceuticals, Inc. Antiviral heterocyclic compounds

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110759860B (zh) * 2018-07-27 2022-10-14 江苏瑞科医药科技有限公司 一种3-甲酸甲酯-4-甲氧基-5-氰基吡啶的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041201A2 (fr) 2002-11-01 2004-05-21 Viropharma Incorporated Composes de benzofurane, compositions et methodes utilisees pour le traitement et la prophylaxie des infections virales induites par l'hepatite c et des maladies associees
US20060189606A1 (en) * 2004-07-14 2006-08-24 Karp Gary M Methods for treating hepatitis C
WO2010030538A2 (fr) * 2008-09-11 2010-03-18 Bristol-Myers Squibb Company Composés destinés au traitement de l'hépatite c
US20100184800A1 (en) * 2008-09-11 2010-07-22 Bristol-Myers Squibb Company Compounds for the Treatment of Hepatitis C

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009523732A (ja) * 2006-01-13 2009-06-25 ピーティーシー セラピューティクス，インコーポレーテッド Ｃ型肝炎の治療方法
AU2008287421A1 (en) * 2007-08-10 2009-02-19 Glaxosmithkline Llc Nitrogen containing bicyclic chemical entities for treating viral infections

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041201A2 (fr) 2002-11-01 2004-05-21 Viropharma Incorporated Composes de benzofurane, compositions et methodes utilisees pour le traitement et la prophylaxie des infections virales induites par l'hepatite c et des maladies associees
US20040162318A1 (en) * 2002-11-01 2004-08-19 Saha Ashis K. Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis C viral infections and associated diseases
US7265152B2 (en) 2002-11-01 2007-09-04 Viropharma Incorporated Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis C viral infections and associated diseases
US20060189606A1 (en) * 2004-07-14 2006-08-24 Karp Gary M Methods for treating hepatitis C
WO2010030538A2 (fr) * 2008-09-11 2010-03-18 Bristol-Myers Squibb Company Composés destinés au traitement de l'hépatite c
US20100184800A1 (en) * 2008-09-11 2010-07-22 Bristol-Myers Squibb Company Compounds for the Treatment of Hepatitis C

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences, 17th edition,", 1985, MACK PUBLISHING COMPANY
BRESSANELLI; S. ET AL., JOURNAL OF VIROLOGY, 2002, pages 3482 - 3492
DEFRANCESCO; RICE, CLINICS IN LIVER DISEASE, vol. 7, 2003, pages 211 - 242
KRIEGER N; LOHMANN V; BARTENSCHLAGER R, J. VIROL., vol. 75, no. 10, 2001, pages 4614 - 4624
LAUER, G. M.; WALKER, B. D., N. ENGL. J. MED., vol. 345, 2001, pages 41 - 52
POYNARD, T. ET AL., LANCET, vol. 352, 1998, pages 1426 - 1432
TALIANI ET AL., ANAL. BIOCHEM., vol. 240, 1996, pages 60 - 67
ZEUZEM, S. ET AL., N. ENGL. J. MED., vol. 343, 2000, pages 1666 - 1672

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103298791B (zh) * 2010-10-20 2016-02-03 生物科学管理有限责任公司 病毒聚合酶抑制剂
CN103298791A (zh) * 2010-10-20 2013-09-11 生物科学管理有限责任公司 病毒聚合酶抑制剂
US8546389B2 (en) 2010-10-20 2013-10-01 Biota Scientific Management Pty Ltd. Viral polymerase inhibitors
JP2013540134A (ja) * 2010-10-20 2013-10-31 ビオタ サイエンティフィック マネージメント ピーティーワイ リミテッド ウイルスポリメラーゼ阻害剤
WO2012051659A1 (fr) * 2010-10-20 2012-04-26 Biota Scientific Management Pty Ltd Inhibiteurs d'une polymérase virale
US8614207B2 (en) 2010-10-26 2013-12-24 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis C virus
US9085587B2 (en) 2010-10-26 2015-07-21 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis C virus
US9309260B2 (en) 2010-10-26 2016-04-12 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis C virus
US8785478B2 (en) 2012-04-11 2014-07-22 Biota Scientific Management Pty Ltd. Viral polymerase inhibitors
US9120775B2 (en) 2012-04-11 2015-09-01 Biota Scientific Management Pty Ltd Viral polymerase inhibitors
WO2014164968A1 (fr) * 2013-03-13 2014-10-09 Bristol-Myers Squibb Company Nouveaux composés pour le traitement de l'hépatite c
US9249152B2 (en) 2014-03-21 2016-02-02 Bristol-Myers Squibb Company Cyano containing azabenzofuran compounds for the treatment of hepatitis C
WO2015143255A1 (fr) * 2014-03-21 2015-09-24 Bristol-Myers Squibb Company Composés azabenzofurane contenant un groupe cyano pour le traitement de l'hépatite c
WO2015169776A1 (fr) 2014-05-08 2015-11-12 Bayer Cropscience Ag Sulfonamides de pyrazolopyridine en tant que nématicides
WO2016022513A1 (fr) * 2014-08-05 2016-02-11 Bristol-Myers Squibb Company Composés furopyridine pour le traitement de l'hépatite c
US9957278B2 (en) 2014-08-05 2018-05-01 Bristol-Myers Squibb Company Furopyridine compounds for the treatment of hepatitis C
US11952389B2 (en) 2015-07-22 2024-04-09 Enanta Pharmaceuticals, Inc. Benzodiazepine derivatives as RSV inhibitors
US10968246B2 (en) 2015-12-18 2021-04-06 Ardelyx, Inc. Substituted 4-phenyl pyridine compounds as non-systemic TGR5 agonists
US10392413B2 (en) 2015-12-18 2019-08-27 Ardelyx, Inc. Substituted 4-phenyl pyridine compounds as non-systemic TGR5 agonists
US11912695B2 (en) 2019-03-18 2024-02-27 Enanta Pharmaceuticals, Inc. Benzodiazepine derivatives as RSV inhibitors
US11572367B2 (en) 2019-10-04 2023-02-07 Enanta Pharmaceuticals, Inc. Antiviral heterocyclic compounds
US11945824B2 (en) 2020-10-19 2024-04-02 Enanta Pharmaceuticals, Inc. Heterocyclic compounds as anti-viral agents
WO2022182861A1 (fr) * 2021-02-26 2022-09-01 Enanta Pharmaceuticals, Inc. Composés hétérocycliques antiviraux
WO2023227698A1 (fr) * 2022-05-25 2023-11-30 Katholieke Universiteit Leuven Nouveaux dérivés pour le traitement de troubles médiés par trpm3
US12006326B2 (en) 2022-08-24 2024-06-11 Enanta Pharmaceuticals, Inc. Antiviral heterocyclic compounds

Also Published As

Publication number Publication date
JP2013522191A (ja) 2013-06-13
JP5572725B2 (ja) 2014-08-13
EP2545050A1 (fr) 2013-01-16
CN102906089A (zh) 2013-01-30
EP2545050B1 (fr) 2014-08-13

Similar Documents

Publication Publication Date Title
US8198449B2 (en) Compounds for the treatment of hepatitis C
US8293909B2 (en) Compounds for the treatment of hepatitis C
EP2545050A1 (fr) Composés destinés au traitement de l'hépatite c
EP2326633B1 (fr) Composés pour le traitement de l'hépatite c
US8354410B2 (en) Compounds for the treatment of hepatitis C
EP2970174B1 (fr) Furanes fusionnes pour le traitement de l'hépatite c
EP2539340B1 (fr) Dérivés de pyrazolopyridazine pour le traitement de l'hépatite c
EP2970322B1 (fr) Nouveaux composés pour le traitement de l'hépatite c
WO2016137832A1 (fr) Nouveaux composés pour le traitement de l'hépatite c
WO2012078545A1 (fr) Dérivés de benzofurane pour le traitement de l'hépatite c
US10214534B2 (en) Substituted 2-phenyl (AZA)benzofuran compounds for the treatment of hepatitis C

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201080066729.9

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10708084

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2012557016

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2010708084

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 7840/CHENP/2012

Country of ref document: IN